A specific interest is graft versus host disease (GVHD), exploring prevention and treatment of acute and chronic GVHD via clinical trials. The objectives of the GVHD trials are to reduce the incidence of GVHD, successfully treat acute and chronic GVHD, identify modalities or agents with more tolerable toxicity profiles and ultimately improve morbidity and mortality of affected patients. To this end, I have established a chronic GVHD clinic within the Stanford BMT division which aids in prospectively identifiing appropriate patients for clinical trials. The chronic GVHD clinic allows comprehensive evaluation and treatment for allogeneic BMT patients with new or progressive CGVHD. Through a multidisciplinary approach with my interested colleagues, I hope to impact the formidable effects GVHD has on the quality of life of the post-allogeneic transplant patient.

Other interests include unrelated donor HCT exploring alternate preparative regimens or graft sources as well as HLA typing.

Protocol For A Research Database For Hematopoietic Stem Cell Transplantation, Other Cellular Therapies and Marrow Toxic InjuriesRecruiting

The primary purpose of the Research Database is to have a comprehensive source of
observational data that can be used to study HSC transplantation.
A secondary purpose of the Research Database is to have a comprehensive source of data to
study marrow toxic injuries.
Objectives:
To learn more about what makes stem cell transplants work well, such as determining the
following:
- how well recipients recover from their transplant
- how recovery after a transplant can be improved
- how access to transplant for different groups of patients can be improved
- how well donors recover from the collection procedures

This phase II trial studies how well giving fluticasone propionate, azithromycin, and
montelukast sodium (FAM) together works in treating patients with bronchiolitis obliterans
who previously underwent stem cell transplant. FAM may be an effective treatment for
bronchiolitis obliterans

Stanford is currently not accepting patients for this trial.For more information, please contact Physician Referrals, 650-723-0822.

Prophylactic Use of Maribavir for the Prevention of Cytomegalovirus (CMV) Disease in Stem Cell Transplant RecipientsNot Recruiting

The purpose of this research study is to investigate whether or not maribavir is safe and
effective for preventing CMV disease when taken by mouth for up to 12 weeks in patients who
have had a stem cell transplant.

Stanford is currently not accepting patients for this trial.For more information, please contact Janice Brown, (650) 723 - 0822.

This phase I/II trial is studying the side effects and best way to give nilotinib when given
together with imatinib mesylate after donor stem cell transplant in treating patients with
acute lymphoblastic leukemia or chronic myelogenous leukemia. Nilotinib and imatinib
mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell
growth.

Stanford is currently not accepting patients for this trial.For more information, please contact Physician Referrals, (650) 723 - 0822.

RATIONALE: Cyclosporine eye drops may prevent graft-versus-host disease of the eye in
patients who have undergone donor stem cell transplant for hematologic cancer or bone marrow
failure disorder.
PURPOSE: This randomized phase I trial is studying how well cyclosporine eye drops work in
preventing graft-versus-host disease of the eye in patients who have undergone donor stem
cell transplant for hematologic cancer or bone marrow failure disorder.

Stanford is currently not accepting patients for this trial.For more information, please contact Joanne Otani, (650) 721 - 2372.

A Phase 3 Study of Brentuximab Vedotin (SGN-35) in Patients at High Risk of Residual Hodgkin Lymphoma Following Stem Cell Transplant (The AETHERA Trial)Not Recruiting

This is a randomized, double-blind, placebo-controlled, multicenter phase 3 trial to
evaluate the efficacy and safety of brentuximab vedotin (SGN-35) and best supportive care
(BSC) compared to placebo and BSC in treatment of residual Hodgkin lymphoma (HL) following
autologous stem cell transplant (ASCT).

Stanford is currently not accepting patients for this trial.For more information, please contact Sarah Robeson, (650) 725 - 1647.

The purpose of the study is to conduct a phase I study of adoptive immunotherapy with
autologous, ex-vivo expanded cytokine-induced killer (CIK) cells to reduce the relapse rate
in autologous stem cell transplant patients with high-risk hematologic malignancies.

Stanford is currently not accepting patients for this trial.For more information, please contact Sherry Moore, (650) 725 - 7951.

Acute myeloid leukemia (AML) is a cancer of the bone marrow that mostly affects older
adults. Even with the best chemotherapy, two-year disease-free survival is achieved in a
minority of patients. Bone marrow transplantation from a sibling donor may improve cure
rates; however, patients over 50 years of age have a high risk of complications and
therefore generally are excluded from this treatment option. Recently our group developed a
transplantation strategy for older cancer patients that protects against
transplant-associated complications, yet does not interfere with the ability of the
transplanted donor cells to destroy cancer cells. With this new method, we can now safely
evaluate transplantation as a curative therapy for AML patients over the age of 50. We have
assembled clinical and scientific researchers throughout the state of California to study
and compare bone marrow transplantation using our new approach with the best standard of
care chemotherapy in AML patients over the age of 50. The results of this study have the
potential to establish a new treatment standard that will improve survival of older AML
patients.

Stanford is currently not accepting patients for this trial.For more information, please contact BMT Referrals, 650-725-1647.

The purpose of the study is to evaluate the feasibility and safety of transplanting CD34+
selected hematopoietic cells from a haploidentical related donor following a
nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin
(ATG).

Stanford is currently not accepting patients for this trial.For more information, please contact BMT Referrals, (650) 723 - 0822.

This pilot clinical trial studies early brief behavioral intervention in treating sleep
disturbance and improving quality of life in patients undergoing bone marrow transplant
(BMT). A brief behavioral intervention may reduce symptoms of insomnia and fatigue and
improve quality of life and cognitive function in patients undergoing BMT

Stanford is currently not accepting patients for this trial.For more information, please contact Oxana Palesh, 650-725-7011.

Single arm, open-label study to provide Defibrotide to patients diagnosed with VOD.
Defibrotide is no longer available though the Emergency Use IND mechanism (also known as
compassionate use, or single patient named use). This protocol is the only mechanism by
which Defibrotide can be made available to patients in the U.S.

Stanford is currently not accepting patients for this trial.For more information, please contact Physician Referrals, 650-723-0822.

The purpose of this study is to (1) demonstrate the efficacy and safety (toxicity) of 25
mg/kg/day of Defibrotide in patients with severe veno-occlusive disease (sVOD) and (2)
evaluate serum and endothelial markers of VOD through the analysis of blood samples.

Stanford is currently not accepting patients for this trial.For more information, please contact BMT Referrals, (650) 723 - 0822.

The study is designed as a Phase III, multicenter trial of tandem autologous transplants
plus maintenance therapy versus the strategy of single autologous transplant plus
consolidation therapy with lenalidomide, bortezomib and dexamethasone (RVD) followed by
maintenance therapy or single autologous transplant plus maintenance therapy as part of
upfront treatment of multiple myeloma (MM). Lenalidomide will be used as maintenance therapy
for three years in all arms.

Stanford is currently not accepting patients for this trial.For more information, please contact Physician Referrals, (650) 723 - 0822.

Autologous Followed by Non-myeloablative Allogeneic Transplantation for Non-Hodgkin's LymphomaNot Recruiting

The purpose of this trial is to develop an alternative treatment for patients with poor risk
non-Hodgkin's lymphoma. This trial uses a combination of high dose chemotherapy with stem
cell transplant using the patient's own cells. This is followed with non-myeloablative
transplant using stem cells from a related or unrelated donor to try and generate an
anti-lymphoma response from the new immune system.

Stanford is currently not accepting patients for this trial.For more information, please contact Physician Referrals, 650-723-0822.

The study objective is to compare the efficacy and safety of US-ATG-F as a supplement to
standard of care prophylaxis versus standard of care prophylaxis alone in moderate to severe
chronic GVHD-free survival.

Stanford is currently not accepting patients for this trial.For more information, please contact Physician Referrals, (650) 723 - 0822.

This study is designed as a combined Phase II/III, randomized, open label, multicenter,
prospective comparative study of sirolimus plus prednisone versus
sirolimus/calcineurin-inhibitor plus prednisone for the treatment of chronic GVHD. Patients
will be stratified by transplant center and will be randomized to an experimental arm of one
of the two pre-specified experimental arms (sirolimus + prednisone or the comparator arm of
sirolimus + calcineurin inhibitor + prednisone) in a 1:1 ratio.

Stanford is currently not accepting patients for this trial.For more information, please contact Physician Referrals, 650-723-0822.

The purpose of this study is to determine the tolerability and efficacy in treating patients
aged 51-60 with acute leukemia and in treating myelodysplastic syndromes (MDS) or
myeloproliferative disorders (MPD).

Stanford is currently not accepting patients for this trial.For more information, please contact BMT Referrals, (650) 723 - 0822.

High -Dose Sequential Therapy and Single Autologous Transplantation for Multiple MyelomaNot Recruiting

This study uses a sequence of high-dose chemotherapy drugs and a stem cell transplant to
treat multiple myeloma. The study is being performed to evaluate the efficacy and side
effects of treatment. Specifically, the study is designed to reduce the risk of interstitial
pneumonitis.

Stanford is currently not accepting patients for this trial.For more information, please contact BMT Referrals, (650) 723 - 0822.

The study is designed as a Phase III, randomized, open label, multicenter, prospective,
comparative trial of granulocyte colony stimulating factor (G-CSF)-mobilized peripheral
blood stem cells (PBSC) versus marrow from unrelated donors for transplantation in patients
with hematologic malignancies. Recipients will be stratified by transplant center and
disease risk and will be randomized to either the PBSC or marrow arm in a 1:1 ratio.

Stanford is currently not accepting patients for this trial.For more information, please contact Kate Tierney, (650) 725 - 7063.

This phase II trial studies how well cluster of differentiation 8 (CD8)+ memory T-cells work
as a consolidative therapy following a donor non-myeloablative hematopoietic cell transplant
in treating patients with leukemia or lymphoma. Giving total lymphoid irradiation and
anti-thymocyte globulin before a donor hematopoietic cell transplant helps stop the growth
of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer
cells. When the healthy stem cells from a donor are infused into the patient they may help
the patient's bone marrow make stem cells, red blood cells, white blood cells, and
platelets. Sometimes the transplanted cells from a donor can make an immune response against
the body's normal cells (called graft-versus-host disease). Giving cyclosporine and
mycophenolate mofetil after the transplant may stop this from happening. Once the donated
stem cells begin working, the patient's immune system may see the remaining cancer cells as
not belonging in the patient's body and destroy them. Giving an infusion of the donor's
white blood cells, such as CD8+ memory T-cells, may boost this effect and may be an
effective treatment to kill any cancer cells that may be left in the body (consolidative
therapy).

Stanford is currently not accepting patients for this trial.For more information, please contact Leah Galvez, 650-725-7951.

The study is designed as a phase III, randomized, open label, multicenter, prospective,
comparative trial of sirolimus and tacrolimus versus tacrolimus and methotrexate as
graft-versus-host disease (GVHD) prophylaxis after human leukocyte antigen (HLA)-matched,
related, peripheral blood stem cell transplantation in individuals with hematologic cancer.
Participants will be stratified by transplant center and will be randomly assigned to the
sirolimus/tacrolimus or tacrolimus/methotrexate arms at a 1:1 ratio.

Stanford is currently not accepting patients for this trial.For more information, please contact BMT Referrals, (650) 723 - 0822.

Chronic graft versus host disease (cGVHD) is a common complication of bone marrow or
hematopoietic cell transplant from another person (allogeneic transplant). This study will
determine if subjects with steroid dependent/refractory cGVHD can tolerate infusion of donor
regulatory T cells and whether their cGVHD responds to the infusion.

This phase II trial studies donor atorvastatin treatment for the prevention of severe acute
graft-versus-host disease (GVHD) in patients undergoing myeloablative peripheral blood stem
cell (PBSC) transplantation. Giving chemotherapy and total-body irradiation (TBI) before a
donor PBSC transplant helps stop the growth of cancer cells. It may also prevent the
patient's immune system reject the donor's stem cells. When the healthy stem cells from a
donor are infused into the patient they may help the patient's bone marrow make stem cells,
red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a
donor can make an immune response against the body's normal cells. Giving atorvastatin to
the donor before transplant may prevent this from happening.

Stanford is currently not accepting patients for this trial.For more information, please contact Leah Galvez, 650-725-7951.

Allogeneic stem cell transplantation (transplant of blood cells from another individual) is
a treatment option for patients with Myelodysplasia or Myeloproliferative Disorders. During
the course of this study, we will attempt to learn whether a particular type of blood cell,
called a Cytokine Induced Killer (CIK) cell may add benefit to allogeneic stem cell
transplantation. CIK cells are present in small quantities in the bloodstream but their
numbers can be expanded after a brief period of nurturing in a laboratory.

Stanford is currently not accepting patients for this trial.For more information, please contact Physician Referrals, 650-723-0822.

The clinical trial is a Phase 1/2a, open-label, multi-center, dose-escalation study to
evaluate the safety, tolerability and pharmacokinetic profile of RGI-2001 in patients
undergoing AHSCT, with radiation or non-radiation myeloablative preparative treatment.
The study will be separated into two parts; a dose escalation phase to assess safety,
followed by a large expansion phase to further evaluate the pharmacologic effects of either
a Maximum Tolerated Dose, Maximum Feasible Dose or optimal pharmacologically active dose of
RGI-2001. The initial dose escalation safety portion of the study (Part 1) will include
higher risk patients and limit the unrelated donor transplants. After safety is established
in part 1 of the study, the second portion of the study will expand the enrollment criteria
and allow transplantation by either related or unrelated donors.
This study will endeavor to identify the dose range at which RGI-2001 has an acceptable
safety profile, at which biologic activity is observed, and to guide possible dose levels to
utilize in later phase studies based on biological activity.

Stanford is currently not accepting patients for this trial.For more information, please contact Physician Referrals, (650) 723 - 0822.

This randomized phase II trial is evaluating how well imatinib mesylate works compared to
rituximab in treating cutaneous sclerosis in patients with chronic graft- versus-host
disease (GVHD). Both imatinib and rituximab have been reported to decrease skin thickening
and improve skin and joint flexibility in people with cutaneous sclerosis due to chronic
GVHD.

Stanford is currently not accepting patients for this trial.For more information, please contact Physician Referrals , 650-723-0822.

Hematopoietic cell transplants (HCT)are one treatment option for people with leukemia or
lymphoma. Family members,unrelated donors or banked umbilical cordblood units with similar
tissue type can be used for HCT. This study will compare the effectiveness of two new types
of bone marrow transplants in people with leukemia or lymphoma: one that uses bone marrow
donated from family members with only partially matched bone marrow; and, one that uses two
partially matched cord blood units.

Non-myeloablative approach for allogeneic transplant is a reasonable option, especially
given that the median age at diagnosis is 55-60 years and frequently present compromised
skin in these patients, which increases the risk of infection. Therefore, we propose a
clinical study with allogeneic HSCT using a unique non-myeloablative preparative regimen,
TLI/ATG, to treat advanced MF/SS.

This phase I trial studies the side effects and best dose of donor regulatory T cells in
treating patients with graft-versus-host disease affecting the liver or gastrointestinal
organs (visceral) within 100 days (acute) after undergoing a stem cell transplant.
Graft-versus-host disease occurs when donor immune cells infused in a stem cell transplant
attack the gut, skin, liver, or other organ systems of the patient. Regulatory T cells are a
type of immune cell that may be able to reduce the attack of the donor's immune cells on the
patient's normal cells and help treat graft-vs-host disease.

Stanford is currently not accepting patients for this trial.For more information, please contact Joanne Otani, 650-721-2372.

Sexuality, Menopausal Symptoms, and Quality of Life in Premenopausal Women in the First Year Following Hematopoietic Cell TransplantationONCOLOGY NURSING FORUMTierney, D. K., Palesh, O., Johnston, L.2015; 42 (5): 488-497

Abstract

To describe sexuality, menopausal symptoms, and quality of life (QOL) in premenopausal women in the first year following hematopoietic cell transplantation (HCT). .One-year prospective longitudinal study..Stanford University Medical Center in California..63 premenopausal female recipients of HCT with a mean age of 34.5 years..Three instruments were used.Sexuality, menopausal symptoms, and QOL..At one year post-HCT, women reported absent to low desire and arousal, adequate lubrication less than half of the time, absent or rare orgasm, pain during vaginal penetration more than half the time, and dissatisfaction with overall sex life. Women also reported moderate to severe vasomotor symptoms, including hot flashes, night sweats, and sweating. Twenty-one women were avoiding sexual activity, and 25 women were not sexually active. Mean QOL scores significantly increased (p = 0.028) in the first year, signifying an improvement in QOL. Variables predictive of improved QOL at one year post-HCT include decreased psychosocial and physical symptoms, sexual satisfaction, and pre-HCT QOL score..One year post-HCT, women reported sexual dysfunction, sexual dissatisfaction, and menopausal symptoms, which negatively affect QOL. .Nurses and other healthcare providers working with recipients of HCT can provide anticipatory guidance on potential changes in sexuality and menopausal symptoms to facilitate adaptation by reducing discordance between expectations and new realities. .

Abstract

The 2006 National Institutes of Health (NIH) Consensus paper presented recommendations by the Ancillary Therapy and Supportive Care Working Group to support clinical research trials in chronic graft-versus-host disease (GVHD). Topics covered in that inaugural effort included the prevention and management of infections and common complications of chronic GVHD, as well as recommendations for patient education and appropriate follow-up. Given the new literature that has emerged during the past 8 years, we made further organ-specific refinements to these guidelines. Minimum frequencies are suggested for monitoring key parameters relevant to chronic GVHD during systemic immunosuppressive therapy and, thereafter, referral to existing late effects consensus guidelines is advised. Using the framework of the prior consensus, the 2014 NIH recommendations are organized by organ or other relevant systems and graded according to the strength and quality of supporting evidence.

Abstract

Grades 2-4 acute graft-versus-host disease (GVHD) occurs in approximately 35% of matched, related donor (MRD) allogeneic hematopoietic cell transplantation (HCT) recipients. We sought to determine if the combination of tacrolimus and sirolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute GVHD and early mortality after allogeneic MRD HCT in a phase 3, multicenter trial. The primary end point of the trial was to compare 114-day grades 2-4 acute GVHD-free survival using an intention-to-treat analysis of 304 randomized subjects. There was no difference in the probability of day 114 grades 2-4 acute GVHD-free survival (67% vs 62%, P = .38). Grades 2-4 GVHD was similar in the Tac/Sir and Tac/Mtx arms (26% vs 34%, P = .48). Neutrophil and platelet engraftment were more rapid in the Tac/Sir arm (14 vs 16 days, P < .001; 16 vs 19 days, P = .03). Oropharyngeal mucositis was less severe in the Tac/Sir arm (peak Oral Mucositis Assessment Scale score 0.70 vs 0.96, P < .001), but otherwise toxicity was similar. Chronic GVHD, relapse-free survival, and overall survival at 2 years were no different between study arms (53% vs 45%, P = .06; 53% vs 54%, P = .77; and 59% vs 63%, P = .36). Based on similar long-term outcomes, more rapid engraftment, and less oropharyngeal mucositis, the combination of Tac/Sir is an acceptable alternative to Tac/Mtx after MRD HCT. This study was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; and the trial was registered at www.clinicaltrials.gov as #NCT00406393.

Abstract

Allogeneic hematopoietic cell transplantation (allo HCT) is the only curative therapy for the myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but treatment toxicity has been a barrier to its more widespread use. The nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) permits the establishment of donor hematopoiesis necessary for the graft-versus-malignancy effect and is protective against acute graft-versus-host disease (aGVHD), but it has minimal direct cytotoxicity against myeloid diseases. We explored the use of TLI-ATG conditioning to treat 61 patients with allo HCT for MDS (n = 32), therapy-related myeloid neoplasms (n = 15), MPN (n = 9), and chronic myelomonocytic leukemia (n = 5). The median age of all patients was 63 years (range, 50 to 73). The cumulative incidence of aGVHD grades II to IV was 14% (95% confidence interval [CI], 4% to 23%) and for grades III to IV, 4% (95% CI, 0 to 9%), and it did not differ between patients who received allografts from related or unrelated donors. The cumulative incidence of nonrelapse mortality (NRM) at 100 days, 12 months, and 36 months was 0%, 7%, and 11%. Overall survival and progression-free survival were 41% (95% CI, 29% to 53%) and 35% (95% CI, 23% to 48%), respectively. The safety and tolerability of TLI-ATG, as exemplified by its low NRM, provides a foundation for further risk-adapted or prophylactic interventions to prevent disease progression.

Abstract

The standard treatment for patients with refractory or relapsed Hodgkin lymphoma (HL) is high-dose chemotherapy and/or radiation with autologous haematopoietic cell rescue (AHCR). In this study, we assessed quality of life and evaluated the risk of late morbidity and mortality for HL patients who underwent AHCR. One hundred and fifty-four patients who underwent AHCR at Stanford University from 1988 to 2002 and survived ?2 years were evaluated. Median follow-up was 10·2 years. There were 54 deaths, 34 from HL, 20 from other causes. The 10-year cumulative incidence of death from HL or other causes was 21·7% and 12·7%, respectively. Thirteen deaths were from second malignancies. The risk ratio of second malignancies was 8·0 [95% confidence interval (CI), 4·7-12·6] compared with the general population, and 3·0 (95% CI, 1·8-4·8) compared with HL patients not undergoing AHCR. The risk ratio of second malignancies was 1·5 (95% CI, 0·9-2·4) compared with HL patients receiving non-AHCR therapy. Overall quality of life did not differ from the general population, but AHCR survivors did note reduced functioning and some worse symptoms. AHCR survivors may be at increased risk of death from HL and other causes compared with the general population, but not compared with the HL population as a whole.

Abstract

Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia.We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37).The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P=0.29), with an absolute difference of 5 percentage points (95% CI, -3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P=0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P=0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse.We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.).

Abstract

B cells are involved in the pathogenesis of chronic GVHD (cGVHD). We hypothesized that prophylactic anti-B-cell therapy delivered 2 months after transplantation would decrease allogeneic donor B-cell immunity and possibly the incidence of cGVHD. Therefore, in the present study, patients with high-risk chronic lymphocytic leukemia (n = 22) and mantle-cell lymphoma (n = 13) received a total lymphoid irradiation of 80 cGy for 10 days and antithymocyte globulin 1.5 mg/kg/d for 5 days. Rituximab (375 mg/m(2)) was infused weekly on days 56, 63, 70, and 77 after transplantation. The incidence of acute GVHD was 6%. The cumulative incidence of cGVHD was 20%. Nonrelapse mortality was 3%. Rituximab treatment after allogeneic transplantation significantly reduced B-cell allogeneic immunity, with complete prevention of alloreactive H-Y Ab development in male patients with female donors (P = .01). Overall survival and freedom from progression at 4 years for chronic lymphocytic leukemia patients were 73% and 47%, respectively; for mantle-cell lymphoma patients, they were 69% and 53%, respectively.

Abstract

We investigated sirolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis in patients with advanced hematological malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from HLA-identical sibling donors. On the basis of pre-study stopping rules, the trial was closed to accrual after enrollment of 11 adult patients. In all, 7 of the 11 patients received BU-containing preparative regimens. Sirolimus was discontinued in three patients because of the toxicity-related events of severe sinusoidal obstructive syndrome, portal vein thrombosis, altered mental status and in one patient because of the risk of poor wound healing. In all, 6 of the 11 patients developed grade II-IV acute GVHD (AGVHD) a median of 15.5 days post HCT. Two of three patients with grade IV AGVHD had sirolimus discontinued by 9 days post HCT. All patients responded to AGVHD therapy without GVHD-related deaths. There were two non-relapse- and two relapse-related deaths. At a median follow-up of 38 months (2-47 months), 7 of 11 patients were alive without disease. MMF and sirolimus GVHD prophylaxis did not reduce the risk of AGVHD, however, there were no GVHD-related deaths. The severe toxicities in the patients receiving the BU-containing preparative regimens limited the continued use of sirolimus and MMF for the prevention of AGVHD.

Abstract

Metastatic breast cancer remains a major treatment challenge. The use of high-dose chemotherapy (HDCT) with rescue by autologous mobilized peripheral blood (MPB) is controversial, in part because of contamination of MPB by circulating tumor cells. CD34(+)Thy-1(+) selected hematopoietic stem cells (HSC) represent a graft source with a greater than 250,000-fold reduction in cancer cells. Here, we present the long-term outcome of a pilot study to determine feasibility and engraftment using HDCT and purified HSC in patients with metastatic breast cancer. Twenty-two patients who had been treated with standard chemotherapy were enrolled into a phase I/II trial between December 1996 and February 1998, and underwent HDCT followed by rescue with CD34(+)Thy-1(+) HSC isolated from autologous MPB. More than 12 years after the end of the study, 23% (5 of 22) of HSC recipients are alive, and 18% (4 of 22) are free of recurrence with normal hematopoietic function. Median progression-free survival (PFS) was 16 months, and median overall survival (OS) was 60 months. Retrospective comparison with 74 patients transplanted between February 1995 and June 1999 with the identical HDCT regimen but rescue with unmanipulated MPB indicated that 9% of patients are alive, and 7% are without disease. Median PFS was 10 months, and median OS was 28 months. In conclusion, cancer-depleted HSC following HDCT resulted in better than expected 12- to 14-year PFS and OS in a cohort of metastatic breast cancer patients. These data prompt us to look once again at purified HSC transplantation in a protocol powered to test for efficacy in advanced-stage breast cancer patients.

Abstract

Stimulatory antiplatelet derived growth factor receptor ? (PDGFRA) antibodies have been associated with extensive chronic graft-versus-host disease (cGVHD). We performed a phase 1 dose escalation trial of imatinib in corticosteroid-dependent/refractory cGVHD to assess the safety of imatinib and test the hypothesis that abrogation of PDGFRA signaling can ameliorate the manifestations of cGVHD. Fifteen patients were enrolled. Mean follow-up time was 56.6 weeks (range, 18-82.4 weeks). Imatinib 400 mg daily was associated with more frequent moderate to life-threatening adverse events than 200 mg daily. The main adverse events were nausea, edema, confusion, diarrhea, liver function test elevation, fatigue, and myalgia. The overall response rate was 40% (6 of 15). The treatment failure rate was 40% (6 of 15). Twenty percent (3 of 15) of subjects had stable disease. Of 4 subjects with phospho-PDGFRA and phospho-PDGFRB immunohistochemistry studies before and after treatment, inhibition of phosphorylation was observed in 3 but correlated with response in one. Anti-PDGFRA antibodies were observed in 7 of 11 evaluable subjects but correlated with clinical activity in 4. We conclude that cGVHD responds to imatinib through multiple pathways that may include PDGFRA signal transduction. This study is registered at www.clinicaltrials.gov as #NCT00760981.

Abstract

The reconstitution of immune function after hematopoietic cell transplant (HCT) plays an important role in the control of viral infections. Both donor and recipient cytomegalovirus (CMV) serostatus has been shown to contribute to effective immune function; however, the influence of a nonmyeloablative preparative (NMA) regimen using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) on antiviral immune reconstitution has not yet been described. In 117 recipients of NMA HCT patients following ATG and TLI, not unexpectedly, CMV viremia was seen in approximately 60% of the seropositive patients regardless of donor serostatus, and recipient seropositivity significantly increased the odds of CMV viremia after transplant in a multivariate analysis. The administration of ATG and TLI resulted in a strikingly earlier viremia in the posttransplant period when compared to the previously reported timing of viremia following myeloablative preparative regimens, especially for transplant recipients who were seropositive for CMV with seronegative donors. Furthermore, early viremia in the setting of a CMV naïve donor was associated with a delay in functional antiviral control. These observations demonstrate the dynamic nature of immunity in relation to CMV antigen exposure in the complex environment resulting from NMA conditions where both donor and residual recipient immune response affect viral control.

Abstract

To assess the long-term clinical course of dry eye in patients with chronic graft-versus-host disease (cGVHD).A prospective case series of 49 patients with cGVHD was conducted. Complete history and ophthalmic examination were performed at baseline and at 36 months (range, 26-53). All patients received treatment for dry eye.Of the 49 participants, 18 (37%) had expired at the time of the 3-year eye examination, 11 were lost to follow-up, 11 declined or were unable to attend the final examination, and 9 (18%) completed the study. There was a statistically insignificant improvement in symptoms of dry eye assessed by the ocular surface disease index [start vs. endpoint: 36 ± 22 (range, 4-72) vs. 30 ± 27 (range, 4-86); P = 0.51]. Visual acuity remained stable at approximately 20/20. Lissamine green staining improved and Schirmer test (with anesthetic) worsened, but neither trend was statistically or clinically significant.Stable visual acuity, tear production, and lissamine green staining and a statistically insignificant improvement in dry eye symptoms were observed in the 9 participants who completed this 3-year prospective case series of 49 patients with cGVHD. Insofar as these patients represent a minority (18%) of the original cohort, their clinical course may not be generalizable to all patients with cGVHD but may still suggest that this patient population's prognosis could be characterized by stability and excellent vision. Sufficiently powered prospective studies are required to validate these postulates.

Abstract

Autologous hematopoietic cell transplantation with augmented BCNU regimens is effective treatment for recurrent or refractory Hodgkin lymphoma (HL); however, BCNU-related toxicity and disease recurrence remain challenges. We designed a conditioning regimen with gemcitabine in combination with vinorelbine in an effort to reduce the BCNU dose and toxicity without compromising efficacy. In this phase I/II dose escalation study, the gemcitabine maximum tolerated dose (MTD) was determined at 1250 mg/m(2), and a total of 92 patients were treated at this dose to establish safety and efficacy. The primary endpoint was the incidence of BCNU-related toxicity. Secondary endpoints included 2-year freedom from progression (FFP), event-free survival (EFS), and overall survival (OS). Sixty-eight patients (74%) had 1 or more previously defined adverse risk factors for transplant (stage IV at relapse, B symptoms at relapse, greater than minimal disease pretransplant). The incidence of BCNU-related toxicity was 15% (95% confidence interval, 9%-24%). Only 2% of patients had a documented reduction in diffusing capacity of 20% or greater. With a median follow-up of 29 months, the FFP at 2 years was 71% and the OS at 2 years was 83%. Two-year FFP was 96%, 72%, 67%, and 14% for patients with 0 (n = 24), 1 (n = 37), 2 (n = 23), or 3 (n = 8) risk factors, respectively. Regression analysis identified PET status pretransplant and B symptoms at relapse as significant prognostic factors for FFP. This new transplant regimen for HL resulted in decreased BCNU toxicity with encouraging FFP and OS. A prospective, risk-modeled comparison of this new combination with other conditioning regimens is warranted.

Abstract

Patients with diffuse large B-cell lymphoma (DLBCL) who do not achieve a complete response to front-line combination chemotherapy are often offered high-dose therapy and autologous hematopoietic cell transplantation (AHCT). However, the efficacy of this therapy in this patient population has been addressed in only a few published reports. We retrospectively analyzed the outcomes of patients with a diagnosis of de novo DLBCL who underwent AHCT at our center between 1988 and 2002, and identified 43 consecutive patients who had not achieved a CR before AHCT, although most showed at least a partial response (PR) to either induction or subsequent salvage chemotherapy. A total of 15 patients received a conditioning regimen that included high-dose chemotherapy with fractionated TBI (FTBI), whereas 28 patients received high-dose chemotherapy only. All autografts were treated ex vivo with MoAbs and complement in an effort to remove any residual malignant B cells. A total of 33 (77%) patients achieved a CR after AHCT. With a median follow-up of 7.3 years, the 5-year OS was 69% and EFS was 59%. Four patients died from non-relapse mortality. By univariate analyses, the following characteristics did not significantly impact OS: disease stage at diagnosis, age-adjusted IPI (International Prognostic Index) score, age > or =40 years, earlier radiotherapy and the use of FTBI in the conditioning regimen. These results confirm the long-term efficacy of AHCT for patients with DLBCL after induction failure.

Abstract

A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)-matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at clinicaltrials.gov under IDs of NCT00185640 and NCT00186615.

Abstract

We conducted a double-blind, randomized multicenter trial to determine whether the addition of mycophenolate mofetil (MMF) improves the efficacy of initial systemic treatment of chronic graft-versus-host disease (GVHD). The primary endpoint was resolution of chronic GVHD and withdrawal of all systemic treatment within 2 years, without secondary treatment. Enrollment of 230 patients was planned, providing 90% power to observe a 20% difference in success rates between the 2 arms. The study was closed after 4 years because the interim estimated cumulative incidence of success for the primary endpoint was 23% among 74 patients in the MMF arm and 18% among 77 patients in the control arm, indicating a low probability of positive results for the primary endpoint after completing the study as originally planned. Analysis of secondary endpoints showed no evidence of benefit from adding MMF to the systemic regimen first used for treatment of chronic GVHD. The estimated hazard ratio of death was 1.99 (95% confidence interval, 0.9-4.3) among patients in the MMF arm compared with the control arm. MMF should not be added to the initial systemic treatment regimen for chronic GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00089141 on August 4, 2004.

Abstract

Germ cell tumors carry an excellent prognosis with platinum-based therapy upfront. The patients who either relapse or demonstrate refractoriness to platinum pose a challenge. There exist many reports in the literature on the use of high-dose chemotherapy and stem cell rescue improving the outcome in patients with relapsed germ cell tumors. However, the reports have great variability in the patient selection, prior treatments, the choice of the conditioning regimen and variability of the doses within the same regimen. In this report, we present 37 patients who underwent a uniform protocol of high-dose chemotherapy with stem cell rescue. Stem cell mobilization was performed with high-dose CY (4 g per m(2)) and we were able to collect adequate cells for marrow rescue in all patients. Patients received a high-dose regimen with etoposide (800 mg/m(2) per day) days -6, -5 and -4 as a continuous infusion, carboplatin (667 mg/m(2) per day) on days -6, -5 and -4 as a 1 h infusion, and CY (60 mg/kg per day) on days -3 and -2. In this high-risk group of patients, high-dose chemotherapy with autologous stem cell rescue led to a 3-year overall survival of 57% and a 3-year event-free survival of 49%. The results are reflective of a single procedure. No tandem transplants were performed. The treatment-related mortality was low at 3% in this heavily pretreated group.

Abstract

Acute graft-versus-host disease (aGVHD) is a constant component of allogeneic hematopoietic cell transplantation (HCT), with variations in incidence and severity affected by the graft source, human leukocyte antigen (HLA) compatibility, and the preparative regimen. The graft source - related versus unrelated donors, bone marrow (BM) versus peripheral blood (PB), umbilical cord blood (UCB) versus unrelated donor BM - are discussed in this review, as well as myeloablative versus reduced-intensity (RI) preparative regimens. Recent comparisons of matched related versus matched unrelated donor HCT support a minimal difference in aGVHD between these two donor sources. The use of BM versus mobilized PB in the matched related donor (MRD) setting has been compared in randomized as well as phase-II comparative clinical trials which support a slight increase in aGVHD in the adult population. Similar results have been seen in the unrelated donor (URD) setting, although based on minimal comparative data to date. Preliminary comparisons of UCB versus URD BM have shown a decreased incidence of aGVHD with UCB, despite increased HLA mismatching. Haploidentical HCT has continued to be explored, with limitations due to delayed immune reconstitution and disease relapse. Many reduced-intensity preparative regimens have been published, with a reduced or minimal difference in incidence of aGVHD when historically compared to myleoablative preparative regimens. More formal comparisons of the different graft sources as well as preparative regimen intensities will be required to determine a more accurate picture of the differences between these transplantation alternatives.

Abstract

Allogeneic hematopoietic cell transplantation (HCT) has been shown to be curative in a group of patients with aggressive non-Hodgkin lymphoma (NHL). A previous study has demonstrated equivalent outcomes with a conditioning regimen based on total body irradiation and another not based on total body irradiation with preparative therapy using cyclophosphamide, carmustine, and etoposide (CBV) in autologous HCT. We investigated the safety and efficacy of using CBV in an allogeneic setting. Patients were required to have relapsed or be at high risk for subsequent relapse of NHL. All patients had a fully HLA-matched sibling donor. Patients received carmustine (15 mg/kg), etoposide (60 mg/kg), and cyclophosphamide (100 mg/kg) on days -6, -4, and -2, respectively, followed by allogeneic HCT. All patients were treated with cyclosporine and methylprednisolone as prophylaxis for graft-versus-host disease (GVHD). Thirty-one patients (median age, 46 years) who were felt to be inappropriate candidates for autologous transplantation were enrolled. Each subject had a median of 3 previous chemotherapy regimens. All patients engrafted. Fifteen of 31 patients are alive. Median follow-up time was 11.5 months (range, .4-126). There were 8 deaths due to relapse. Nonrelapse mortality (n = 8) included infection (n = 3), GVHD (n = 2), diffuse alveolar hemorrhage (n = 1), veno-occlusive disease in the setting of concurrent acute GVHD of the liver (n = 1), and leukoencephalopathy (n = 1). Probabilities of event-free survival and overall survival were, respectively, 44% (95% confidence interval, 26%-62%) and 51% (33%-69%) at 1 year and 44% (26%-62%) and 47% (29%-65%) at 5 years. Probability of relapse was 33% (15%-51%) at 1 year and 5 years. Probability of nonrelapse mortality was 31% (13%-49%) at 1 year and 5 years. Incidences were 29% for acute GVHD and 39% for chronic GVHD. None of the 12 patients who developed chronic GVHD has disease recurrence. Patients who had required >3 previous chemotherapy regimens before HCT had an increased probability of relapse. CBV is an effective preparative regimen for patients with aggressive NHL who undergo allogeneic HCT.

Abstract

Conditioning with total lymphoid irradiation plus antithymocyte serum protects mice against acute graft-versus-host disease (GVHD) after hematopoietic-cell transplantation. We tested this strategy in humans.Thirty-seven patients with lymphoid malignant diseases or acute leukemia underwent an experimental conditioning regimen with 10 doses of total lymphoid irradiation (80 cGy each) plus antithymocyte globulin, followed by an infusion of HLA-matched peripheral-blood mononuclear cells from related or unrelated donors who received granulocyte colony-stimulating factor.Of the 37 transplant recipients, only 2 had acute GVHD after hematopoietic-cell transplantation. Potent antitumor effects in patients with lymphoid malignant diseases were shown by the change from partial to complete remission. In the transplant recipients who underwent conditioning with total lymphoid irradiation and antithymocyte globulin, the fraction of donor CD4+ T cells that produced interleukin-4 after in vitro stimulation increased by a factor of five, and the proliferative response to alloantigens in vitro was reduced, as compared with normal control subjects and control subjects who underwent conditioning with a single dose of total-body irradiation (200 cGy).A regimen of total lymphoid irradiation plus antithymocyte globulin decreases the incidence of acute GVHD and allows graft antitumor activity in patients with lymphoid malignant diseases or acute leukemia treated with hematopoietic-cell transplantation.

Abstract

Lesions caused by verrucus vulgaris are commonly refractory to therapy and may become large, painful, or disfiguring in immunocompromised patients. Cidofovir is a potent nucleoside analog antiviral agent shown to have in vitro and in vivo activity against a broad spectrum of DNA viruses. We report a successful use of topical cidofovir to treat verruca vulgaris lesions in a highly immunocompromised patient, who was not considered a candidate for conventional therapy.

Abstract

We conducted a phase II trial in 19 chronic graft-versus-host disease (cGVHD) patients with rapamycin, calcineurin inhibitors, and prednisone with the goals of controlling cGVHD, reducing prednisone use, and defining the safety of this regimen. Rapamycin was begun as second-line (n = 9) or more than second-line (n = 10) therapy. With a median follow-up of 42 months, 16 patients were evaluable for response. Nine patients discontinued rapamycin because of poor compliance/patient request (n = 2) or an adverse event (n = 7), 3 of whom were not evaluable because of withdrawal at < or =1 month or noncompliance. The adverse events included serum creatinine > or =2.4 mg/dL (n = 4), hemolytic uremic syndrome (n = 2), and relapse of malignancy (n = 1). Fifteen of 16 evaluable patients had a clinical response. Five of the 16 discontinued the drug, and 1 died of relapsed leukemia. Of the 10 patients who continued rapamycin, 2 discontinued and 1 successfully tapered all systemic immunosuppression. Three of the 10 developed progressive cGVHD with tapering immunosuppression; all responded to resumption of prior medications. Four of the 10 patients required alternate therapy for persistent or progressive cGVHD while receiving rapamycin; prednisone was discontinued (n = 2) or tapered at the time of progressive disease (n = 2). Seventeen of 19 original patients were alive. One death was due to relapsed malignancy, and 1 was due to congestive heart failure. In this report of rapamycin as cGVHD therapy, there is evidence of rapamycin's efficacy. Given the significant toxicities described, investigation of altered administration of rapamycin and calcineurin inhibitors should be pursued in future cGVHD trials.

Abstract

The differences in toxicity of etoposide following continuous or bolus infusion are unknown.We studied the schedule-dependent toxicity of high-dose etoposide when combined with high-dose cytarabine and idarubicin (IDEA) in 138 patients with acute leukemia. Four groups of patients were studied: group I, relapse; group II, secondary acute myeloid leukemia (AML); group III, de novo AML, age >60 years; and group IV, induction failure or blast crisis of myeloproliferative syndrome. Treatment for groups I-III was idarubicin 8 mg/m(2) per day days 1-3, cytarabine 2000 mg/m(2) once a day days 1-6, and etoposide 1600 mg/m(2) total dose. Group IV treatment differed by cytarabine given twice daily days 1-6. Patients were randomized to etoposide as a continuous infusion days 1-6 or as a bolus infusion over 10 h on day 7.Continuous infusion etoposide produced significantly more oral mucositis than bolus etoposide. In groups I-III, comparing continuous and bolus etoposide, there was a median of 3 vs 0 days of grade 2 or more oral mucositis (P<0.0001) and 13.5 vs 0 days of total parenteral nutrition (TPN) (P=0.0003). Group IV patients had a median 7 vs 0 days of grade 2 or more oral mucositis (P<0.01) and 21 vs 7 days of TPN (P<0.003), respectively. There were no differences in hematologic recovery, length of hospital stay, complete remission rate or overall survival between the two etoposide schedules. Of groups I-III patients, 51% achieved complete remission, and 11% died from treatment-related complications.The toxicity profile of high-dose etoposide is schedule-dependent with prolonged exposure producing significantly more non-hematologic toxicity.

Abstract

In a previous multicenter phase III trial comparing peripheral blood stem cell transplantation (PBSCT) to bone marrow transplantation (BMT) from HLA-matched related donors, we found no statistically significant difference in the cumulative incidence of clinical extensive chronic graft-versus-host disease (GVHD) in the 2 groups. We have analyzed the results in more detail to determine whether the clinical characteristics of chronic GVHD after PBSCT might be distinct from those that occur after BMT. Clinical extensive chronic GVHD developed in 39 of 63 recipients of PBSCs and in 32 of 63 BM recipients who were alive and free of malignancy at day 100 after the transplantation. No significant differences were found in the time and type of onset of clinical extensive chronic GVHD or in the frequency of complications associated with severe morbidity. Involvement of skin and female genital tract was more frequent in PBSC recipients than in BM recipients. The cumulative incidence of chronic GVHD at 3 years was similar in the 2 groups, but the number of successive treatments needed to control chronic GVHD was higher after PBSCT than after BMT (P =.03), and the duration of glucocorticoid treatment was longer after PBSCT compared to BMT (P =.03). These results suggest that chronic GVHD after PBSCT may be more protracted and less responsive to current treatment than chronic GVHD after BMT. Assessment of the overall benefits of PBSCT compared to BMT will require continued long-term follow up of morbidity associated with chronic GVHD.

Abstract

A retrospective analysis was performed to investigate the outcome of high-dose therapy (HDT) and autologous hematopoietic cell transplantation in patients with follicular lymphomas beyond first remission. Ninety-two patients with primary induction failure or relapsed follicular low-grade lymphoma (FLGL), follicular large cell lymphoma (FLCL), and transformed follicular lymphoma (TFL) were treated with myeloablative therapy consisting of etoposide (60 mg/kg), cyclophosphamide (100 mg/kg), and either carmustine (BCNU;15 mg/kg) or fractionated total body irradiation (FTBI; 1200 cGy) followed by transplantation of purged autologous bone marrow or peripheral blood hematopoietic cells. For the 49 patients with relapsed FLGL, the median age was 49 years and the median interval from diagnosis to HDT was 30 months. The 4-year estimate of overall survival (OS) was 60% (95% confidence interval [CI], 45%-75%) and of disease-free survival (DFS) was 44% (95% CI, 29%-59%). Treatment with the FTBI-containing HDT regimen was associated with significantly longer DFS (P = .04) and OS (P = .04) in our multivariate analysis. OS was also significantly longer among those treated with 3 or fewer chemotherapy regimens. For the 26 FLCL patients, the median age was 51 years and in 31% the indication for HDT was primary induction failure. For FLCL patients, the 4-year estimate of OS was 58% (95% CI, 37%-79%) and of DFS was 51% (95% CI, 30%-72%). Among the 17 patients with TFL, 13 (76%) transformed at first relapse, and only 6 patients (35%) achieved complete remission with salvage therapy prior to HDT. For TFL patients, the 4-year estimate of OS was 50% (95% CI, 24%-76%) and of DFS 49% (95% CI, 20%-78%). There were 3 occurrences of myelodysplasia (1 after treatment with TBI, 2 after BCNU treatment), yielding an estimated incidence of 7% (95% CI, 0%-16%) at 56 months. This analysis shows that relapsed FLGL patients treated with 3 or fewer different chemotherapy regimens show inferior survival. The HDT regimen containing FTBI appears to be superior to the BCNU-based regimen for relapsed FLGL, although longer follow-up is needed to evaluate late effects. Lastly, patients with TFL or induction failure and relapsed FLCL can achieve survival outcome comparable to those observed with the indolent follicular lymphomas.